(A) Field of the Invention
The present invention is directed to a method for selecttively depositing for diagnostic purposes radiopharmaceutical compounds in target tissues or organs of a mammal. Mammal as used herein includes the human being. The invention more particularly relates to radiopharmaceutical compounds which are capable of selective accumulation in tissues or organs having lowered intracellular pH as a result of normal metabolism or diseased state.
(B) Description of the Prior Art
Radiopharmaceutical compounds have been in use for diagnostic purposes for a long time. Those well versed in the art relating to radiopharmaceuticals and nuclear medicine are well aware of the requirements which must be satisfied by a diagnostically useful radiopharmaceutical compound. Briefly, these requirements include the following. The radiopharmaceutical compound must be able to penetrate into a target tissue of organ and attain a sufficiently high concentration therein so that its presence is detectable by state of the art radiation monitoring means. The accumulation of the radiopharmaceutical compound in the target tissue or organ must be sufficiently selective relative to other tissues and organs of the body so that a diagnostic distinction for its presence in the target tissue or organ relative to the other tissues or organs can be made. Furthermore, the radiopharmaceutical compound must emit radiation capable of penetrating through several other tissues or organs of the body. Experience has shown that only radiopharmaceutical compounds emitting .gamma., X-ray or positron radiation satisfy this requirement. Finally, and preferably, a diagnostic radiopharmaceutical compound should be easily prepared from inexpensive and available radionuclides.
In order to gain the desired tissue or organ penetration and uptake specificity for a radiopharmaceutical compound, various physiological processes and phenomena have been exploited in the past. For example, radioactive compounds which are excreted or detoxified by the liver or kidney may accumulate in these organs long enough for permitting a diagnosis of liver or kidney malfunctions. Other radiopharmaceutical compounds may depend on a selective transport mechanism through the cell membranes for entry into the cells of the target tissue or organ. An example of such a compound is F-18 2-fluoro-2-deoxyglucose which, being a close structural analog of the ubiquitous metabolite glucose, enters cells through the existing active transport mechanism for glucose. Once inside the cell, F-18 2-fluoro-2-deoxyglucose undergoes phosphorylation to yield the corresponding 6-phosphate. F-18 2-fluoro-2-deoxyglucose 6-phosphate, however, does not enter the conventional metabolic pathways of glucose 6-phosphate and due to its state of ionization, is incapable of rapidly exiting from the cells by passive diffusion through the cell membranes. Consequently, it is effectively trapped within the cells. F-18 2-fluoro-2-deoxyglucose, by mimicking the natural metabolite glucose, is capable of crossing the blood brain barrier and therefore has been found suitable for radiopharmaceutical mapping of the brain. The structures of radiopharmaceutical compounds, depending upon selective transport mechanisms, are obviously very limited since the cell must recognize the structure of the compound as being desirable for the cell.
Another example of radiopharmaceutical compound which freely crosses cell membranes and thereafter is rather effectively trapped within the cells is N-13 labeled ammonia. After entry into the cells, N-13 labeled ammonia is enzymatically converted into amino acids and other metabolites which are incapable of diffusing out of the cell. For a detailed description of the biodistribution and metabolism of F-18 2-fluoro-2-deoxy-glucose and N-13 labeled ammonia reference is made to the following publications:
Gallagher BM, Fowler JS, Gutterson NI, et al.: Metabolic Trapping as a Principle of Radiopharmaceutical Design: Some Factors Responsible for the Biodistribution of (.sup.18 F) 2-deoxy-2-fluoro-D-glucose, J. Nucl Med 19:1154-1161, 1978; Phelps ME, Hoffman EJ, Rayband C: Factors which Affect Cerebral Uptake and Retention of .sup.13 NH.sub.3, Stroke 8: 694-701, 1977; Gallagher BM, Ansari A, Atkins H., et al.: Radiopharmaceuticals XXVI. .sup.18 F-labeled 2-deoxy-2fluoro-D-glucose as a Radiopharmaceutical for Measuring Regional Myocardial Glucose Metabolism in vivo: Tissue Distribution and Imaging Studies in Animals, J Nucl Med 18: 990-996, 1977; Carter CC, Lifton JF, Welch MJ: Oxygen Uptake and Blood pH and Concentration Effects of Ammonia in Dogs Determined with Ammonia Labeled with 10 Minutes Half-lived Nitrogen-13, Neurology 23: 204-213, 1973; Phelps ME, Hoffman EJ, Selin C, et al.: Investigation of (.sup.18 F) 2-fluoro-2-deoxyglucose for the Measure of Myocardial Glucose Metabolism, J. Nuc. Med. 19: 1311-1319; Tewson TJ, Welch MJ, Raichle ME: (.sup.18 F)-Labeled 3-deoxy-3-fluoro-D-glucose: Synthesis and Preliminary Biodistribution Data, J. Nuc. Med. 19: 1339-1345.
In the above cited article authored by Phelps et al., Stroke 8: 694-701, 1977, it was recognized that ammonia is capable of penetrating the blood brain barrier only in the form of free ammonia (NH.sub.3) and not as ammonium ion. Furthermore, this article has reiterated the teachings of the prior art that a strong correlation exists between lipid solubility characteristics of a compound, as measured by oil-water partition coefficients, and the blood brain barrier penetration capability of the compound. A significant disadvantage of radiopharmaceuticals bearing F-18 labeled fluorine or N-13 labeled nitrogen is that these radionuclides are not generally available.
Other radiopharmaceutical compounds have been designed which take advantage of lipid solubility to permit the compound to enter the organ or tissue. See e.g. Michael D. Loberg et al.: Membrane Transport of Tc-99m-Labeled Radiopharmaceuticals. I. Brain Uptake by Passive Transport: J. Nucl. Med. Vol. 20, No. 11, pp 1181-1188. Most of the compounds described in the Loberg et al. article nevertheless have ionic substituents and have no means for enhancing their retention within the cellular structure of the organ or tissue. Other such compounds use various isotopes of iodine as the radioactive component (radionuclide) of the radiopharmaceutical compound. Some of such iodine containing compounds are believed to have taken advantage of lipid solubility in order to enter the cell and, although not recognized in the prior art, some may have even inherently been held within an organ or tissue due to a drop in pH. An example of such a prior art iodine containing compound which may have such previously unrecognized properties is 1,4,-(di methylamino)-methyl-3-iodobenzene. Unfortunately the most desirable isotope of iodine, .sup.123 I, is not readily available. Furthermore, radioactive iodine is known to accumulate in the thyroid which is undesirable. Therefore when isotopes of iodine are used additional medical method steps are required to reduce or prevent such accumulations.
As was briefly pointed out above, the prior art has designed several radiopharmaceutical compounds which exploit various differences in metabolic or physiological states of the several tissues of the body for diagnostic purposes. The prior art, however, has not yet knowingly designed or recognized that radiopharmaceutical compounds could be designed which utilize differences between the pH of the blood and the intracellular pH of various organs or tissues to retain the compound within the organ or tissue. This is true in spite of the fact that the brain, as well as several actively metabolizing tissues such as the heart and some tumors, have been known to possess a lower intracellular pH than the blood stream. Furthermore, regional pH differences within an organ have been shown to exist due to local ischemia or other abnormal metabolic states. The relative difference between the intracellular pH of certain tissues or organs of the body compared to other tissues, organs or the bloodstream is termed for the purposes of the present description, regional pH shift.
For a detailed discussion of the intracellular pH and regional pH shift within the various organs and tissues of the human body, reference is made to an article by W. J. Waddell and R. G. Bates titled "Intracellular pH", Physiological Review 49: 286-329, 1969.